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Dopaminergic and behavioural changes in a loss‐of‐imprinting model of Cdkn1c

The imprinted gene Cdkn1c is expressed exclusively from the maternally inherited allele as a consequences of epigenetic regulation. Cdkn1c exemplifies many of the functional characteristics of imprinted genes, playing a role in foetal growth and placental development. However, Cdkn1c also plays an i...

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Autores principales: McNamara, G. I., Davis, B. A., Browne, M., Humby, T., Dalley, J. W., Xia, J., John, R. M., Isles, A. R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836939/
https://www.ncbi.nlm.nih.gov/pubmed/28857482
http://dx.doi.org/10.1111/gbb.12422
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author McNamara, G. I.
Davis, B. A.
Browne, M.
Humby, T.
Dalley, J. W.
Xia, J.
John, R. M.
Isles, A. R.
author_facet McNamara, G. I.
Davis, B. A.
Browne, M.
Humby, T.
Dalley, J. W.
Xia, J.
John, R. M.
Isles, A. R.
author_sort McNamara, G. I.
collection PubMed
description The imprinted gene Cdkn1c is expressed exclusively from the maternally inherited allele as a consequences of epigenetic regulation. Cdkn1c exemplifies many of the functional characteristics of imprinted genes, playing a role in foetal growth and placental development. However, Cdkn1c also plays an important role in the brain, being key to the appropriate proliferation and differentiation of midbrain dopaminergic neurons. Using a transgenic model (Cdkn1c (BACx1)) with a twofold elevation in Cdkn1c expression that mimics loss‐of‐imprinting, we show that increased expression of Cdkn1c in the brain gives rise to neurobiological and behavioural changes indicative of a functionally altered dopaminergic system. Cdkn1c (BACX1) mice displayed altered expression of dopamine system‐related genes, increased tyrosine hydroxylase (Th) staining and increased tissue content of dopamine in the striatum. In addition, Cdkn1c (BACx1) animals were hypersensitive to amphetamine as showed by c‐fos expression in the nucleus accumbens. Cdkn1c (BACX1) mice had significant changes in behaviours that are dependent on the mesolimbic dopaminergic system. Specifically, increased motivation for palatable food stuffs, as indexed on a progressive ratio task. In addition, Cdkn1c (BACX1) mice displayed enhanced social dominance. These data show, for the first time, the consequence of elevated Cdkn1c expression on dopamine‐related behaviours highlighting the importance of correct dosage of this imprinted gene in the brain. This work has significant relevance for deepening our understanding of the epigenetic factors that can shape neurobiology and behaviour.
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spelling pubmed-58369392018-03-12 Dopaminergic and behavioural changes in a loss‐of‐imprinting model of Cdkn1c McNamara, G. I. Davis, B. A. Browne, M. Humby, T. Dalley, J. W. Xia, J. John, R. M. Isles, A. R. Genes Brain Behav Original Articles The imprinted gene Cdkn1c is expressed exclusively from the maternally inherited allele as a consequences of epigenetic regulation. Cdkn1c exemplifies many of the functional characteristics of imprinted genes, playing a role in foetal growth and placental development. However, Cdkn1c also plays an important role in the brain, being key to the appropriate proliferation and differentiation of midbrain dopaminergic neurons. Using a transgenic model (Cdkn1c (BACx1)) with a twofold elevation in Cdkn1c expression that mimics loss‐of‐imprinting, we show that increased expression of Cdkn1c in the brain gives rise to neurobiological and behavioural changes indicative of a functionally altered dopaminergic system. Cdkn1c (BACX1) mice displayed altered expression of dopamine system‐related genes, increased tyrosine hydroxylase (Th) staining and increased tissue content of dopamine in the striatum. In addition, Cdkn1c (BACx1) animals were hypersensitive to amphetamine as showed by c‐fos expression in the nucleus accumbens. Cdkn1c (BACX1) mice had significant changes in behaviours that are dependent on the mesolimbic dopaminergic system. Specifically, increased motivation for palatable food stuffs, as indexed on a progressive ratio task. In addition, Cdkn1c (BACX1) mice displayed enhanced social dominance. These data show, for the first time, the consequence of elevated Cdkn1c expression on dopamine‐related behaviours highlighting the importance of correct dosage of this imprinted gene in the brain. This work has significant relevance for deepening our understanding of the epigenetic factors that can shape neurobiology and behaviour. Blackwell Publishing Ltd 2017-09-15 2018-02 /pmc/articles/PMC5836939/ /pubmed/28857482 http://dx.doi.org/10.1111/gbb.12422 Text en © 2017 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
McNamara, G. I.
Davis, B. A.
Browne, M.
Humby, T.
Dalley, J. W.
Xia, J.
John, R. M.
Isles, A. R.
Dopaminergic and behavioural changes in a loss‐of‐imprinting model of Cdkn1c
title Dopaminergic and behavioural changes in a loss‐of‐imprinting model of Cdkn1c
title_full Dopaminergic and behavioural changes in a loss‐of‐imprinting model of Cdkn1c
title_fullStr Dopaminergic and behavioural changes in a loss‐of‐imprinting model of Cdkn1c
title_full_unstemmed Dopaminergic and behavioural changes in a loss‐of‐imprinting model of Cdkn1c
title_short Dopaminergic and behavioural changes in a loss‐of‐imprinting model of Cdkn1c
title_sort dopaminergic and behavioural changes in a loss‐of‐imprinting model of cdkn1c
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836939/
https://www.ncbi.nlm.nih.gov/pubmed/28857482
http://dx.doi.org/10.1111/gbb.12422
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